calpain and Genetic-Diseases--Inborn

This review was written in memory of our late friend, Dr. Hiroyuki Sorimachi, who, following the steps of his mentor Koichi Suzuki, a pioneer in calpain research, has made tremendous contributions to the field. During his career, Hiro also wrote several reviews on calpain, the last of which, published in 2016, was comprehensive. In this manuscript, we decided to put together a review with the basic information a novice may need to know about calpains. We also tried to avoid similarities with previous reviews and reported the most significant new findings, at the same time highlighting Hiro's contributions to the field. The review will cover a short history of calpain discovery, the presentation of the family, the life of calpain from transcription to activity, human diseases caused by calpain mutations and therapeutic perspectives.

Topics: Calpain; Genetic Diseases, Inborn; Genetic Therapy; Humans; Lysosomes; Mutation; Proteasome Endopeptidase Complex; Proteolysis

A single amino acid mutation near the active site of the CAPN5 protease was linked to the inherited blinding disorder, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #193235). In homology modeling with other calpains, this R243L CAPN5 mutation was situated in a mobile loop that gates substrate access to the calcium-regulated active site. In in vitro activity assays, the mutation increased calpain protease activity and made it far more active at low concentrations of calcium. To test whether the disease allele could yield an animal model of ADNIV, we created transgenic mice expressing human (h) CAPN5(R243L) only in the retina. The resulting hCAPN5(R243L) transgenic mice developed a phenotype consistent with human uveitis and ADNIV, at the clinical, histological and molecular levels. The fundus of hCAPN5(R243L) mice showed enhanced autofluorescence (AF) and pigment changes indicative of reactive retinal pigment epithelial cells and photoreceptor degeneration. Electroretinography showed mutant mouse eyes had a selective loss of the b-wave indicating an inner-retina signaling defect. Histological analysis of mutant mouse eyes showed protein extravasation from dilated vessels into the anterior chamber and vitreous, vitreous inflammation, vitreous and retinal fibrosis and retinal degeneration. Analysis of gene expression changes in the hCAPN5(R243L) mouse retina showed upregulation of several markers, including members of the Toll-like receptor pathway, chemokines and cytokines, indicative of both an innate and adaptive immune response. Since many forms of uveitis share phenotypic characteristics of ADNIV, this mouse offers a model with therapeutic testing utility for ADNIV and uveitis patients.

Topics: Animals; Calpain; Cell Line; Genetic Diseases, Inborn; Humans; Inflammation; Mice; Mice, Transgenic; Uveitis

To detect the association among calpain-10(CAPN-10) gene polymorphism, hypentension and hyperglycemia.. 378 individuals in the present study were the second generation offsprings of 187 hypentensives and 19 1 nonhypertensives. Fasting plasma glucose (FPG), insulin, triglyceride and fibrinogen were determined. The polymorphism of UCSNP-43 and UCSNP-44 of CAPN 10 gene were analysed with PCR-SSCP method.. (1)The frequency of G/G geno type of UCSNP-43 was higher in the second generation offsprings of the hypertensives than that in the nonhypertensive controls(86.6%, 75.4%, P < 0.05). (2) The frequenncy of G/G genotype of UCSNP-43 was higher in the hypertensive parents of the second generation offsprings in the hypertensive groups than that in the normotensive parent of the second generation offsprings of the nonhypertensive control groups (OR = 2.84, P = 0.01). After adjustment of age, sex and body mass index (BMI), the frequency of G/G genotype in the highest FPG-quartiles (FPG 5.42 +/- 0.1mmol/L) was much more than that in the lowest FPG quartiles (FPG 4.09 +/- 0.3 mmol/L) with OR of 3.32.. Polymorphism of UCSNP-43 in CAPN-10 gene might be one of the genetic factors contributing to hypertension and diabetes mellitus in the population in Daqing city. It may be a predictor of type 2 diabetes mellitus (T2DM) in the decendents of hypertensives.

Topics: Adult; Age Factors; Blood Glucose; Calpain; Female; Fibrinogen; Gene Frequency; Genetic Diseases, Inborn; Humans; Hyperglycemia; Hypertension; Insulin; Male; Polymorphism, Genetic; Sex Factors; Triglycerides

Our understanding of early human development has been impeded by the general difficulty in obtaining suitable samples for study. As a result, and because of the extraordinarily high degree of evolutionary conservation of many developmentally important genes and developmental pathways, great reliance has been placed on extrapolation from animal models of development, principally the mouse. However, the strong evolutionary conservation of coding sequence for developmentally important genes does not necessarily mean that their expression patterns are as highly conserved. The very recent availability of human embryonic samples for gene expression studies has now permitted for the first time an assessment of the degree to which we can confidently extrapolate from studies of rodent gene expression patterns. We have found significant human-mouse differences in embryonic expression patterns for a variety of genes. We present detailed data for two illustrative examples. Wnt7a, a very highly conserved gene known to be important in early development, shows significant differences in spatial and temporal expression patterns in the developing brain (midbrain, telencephalon) of man and mice. CAPN3, the locus for LGMD2A limb girdle muscular dystrophy, and its mouse orthologue differ extensively in expression in embryonic heart, lens and smooth muscle. Our study also shows how molecular analyses, while providing explanations for the observed differences, can be important in providing insights into mammalian evolution.

Topics: 5' Untranslated Regions; Amino Acid Sequence; Animals; Base Sequence; Brain; Calpain; Embryonic and Fetal Development; Exons; Gene Expression Regulation, Developmental; Genes; Genetic Diseases, Inborn; Humans; Isoenzymes; Mice; Molecular Sequence Data; Muscle Proteins; Peptide Fragments; Promoter Regions, Genetic; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins; Species Specificity; Wnt Proteins